Table 1.

Proposed mechanisms of vaccine‐induced immune thrombocytopaenia and thrombosis (VITT) induced by adenoviral vector COVID‐19 vaccines

Proposed mechanisms	Counterarguments
Platelet activation is directly mediated by AVVs and/or their constituents 23	CXCL4(PF4) autoantibodies should not be required for platelet activation. Unlikely AVVs are present in high enough quantity to cause massive platelet activation
CXCL4(PF4) autoantibodies result from antigen molecular mimicry between SARS‐CoV‐2 SP and CXCL4(PF4)	Other SARS‐CoV‐2 SP vaccines do not induce CXCL4(PF4) autoantibodies. Antigenic cross‐reactivity between SARS‐CoV‐2 SP and CXCL4(PF4) has not been demonstrated 24
Binding of DNA from AVVs to CXCL4(PF4) results in neoepitope formation in CXCL4(PF4) that induces autoantibody production 25	DNA vaccines not previously associated with autoimmunity 25
AVV constituents form antigenic complexes with CXCL4(PF4), which induces an autoantibody response against CXCL4(PF4) promoted by pro‐inflammatory vaccine constituents and increased vascular permeability caused by vaccine‐derived EDTA 26	Proposed mechanism does not involve heparin or heparan, which appear to be important because autoantibody binding is restricted to amino acids located within the heparin binding site on CXCL4(PF4) 27
Transduction of vascular endothelial cells with AAV‐derived DNA leads to luminal expression of SARS‐CoV‐2 SP, resulting in recruitment and activation of platelets that secrete CXCL4(PF4), which becomes immunogenic after binding to HSPG derived from vascular endothelial cells 17	Unclear whether vascular endothelial cells at vaccination sites express SARS‐CoV‐2 SP in vivo

AVV, adenoviral vector vaccine; CXCL4, chemokine (C‐X‐C motif) ligand 4; HSPG, heparan sulphate proteoglycans; PF4, platelet factor 4; SP, spike protein.